Adoptive immunotherapy of cancer contemplates direct stimulation of the host immune response to tumor through vaccination with specific tumor cells and/or administration of more general immune stimulants. Several factors can impede an adequate anti-tumor immune response, however, including the lack of a suitable tumor-associated antigen, defective antigen processing, production of immunologically suppressive factors by the tumor, and the like.
Adoptive immunotherapy attempts to overcome tumor-mediated host immune suppression by administering immunologically active cells or antibodies directly to the tumor-bearing host. In adoptive cell therapy approaches, immune effector cells are isolated from a tumor-bearing host and activated and/or expanded ex vivo prior to reinfusion. Autologous NK cells, for example, have been activated ex vivo with recombinant interleukin-2 (IL-2) to enhance CD56+ natural killer (NK) cell cytotoxicity (Lather et al. (1985) Journal of Immunology 134, 794-801) and generate lymphokine activated killer (LAK) cells, which are capable of killing fresh autologous and allogeneic human tumor cells in vitro. (Rayner, et al. (1985) Cancer 55, 1327-1333). The administration of LAK cells, typically in combination with systemic IL-2 infusion, has been repeatedly investigated as an adoptive immunotherapy for human cancer.
Unfortunately, however, these LAK cell therapies have met with only limited success in the clinic. Autologous cells must first be obtained from the patient and successfully expanded ex vivo to a cell count sufficient for therapy. Moreover, the LAK cells must be continuously exposed to IL-2 in order to maintain their activated state and, accordingly, effective clinical protocols generally require high-dose systemic IL-2 administration in conjunction with the cell therapy. Although some anti-tumor effects were obtained in some patients, toxicities resulting from the IL-2 co-administration were a significant problem (Vieweg et al. (1995) Cancer Investigation 13:193-201), including fever, chills, malaise, arthralgias, myalgias, and weight gain from fluid retention (Lotze, et al. (1985) J. Immunology 135: 2865-2875).
Successful implementation of LAK cell therapy is also hampered by the inability to employ the activated LAK cells other than in real-time, individualized protocols. In particular, special equipment and dedicated laboratories are necessary to isolate, expand and reinfuse each patient's cells. Moreover, LAK cell activity is significantly impaired within twelve hours after removal of IL-2 and, accordingly, once activated, the LAK cells must be promptly infused before the activation state is lost. Significantly, preservation of LAK cells necessitates that LAK cells be prepared for administration by re-stimulation with IL-2 to re-establish the activated state. (Kawai et al. (1988) Transfusion 28:531-5; Schiltz et al. (1998) J. Immunother. 20:377-86). Accordingly, the administration of LAK cells for the immunotherapy of cancer has had limited clinical impact and acceptance, requiring expensive, individualized and labor intensive methods for isolation and expansion, and real-time administration to avoid loss of activation.
What is needed, therefore, are activated immune effector cell populations having more reliable and durable activity that can better facilitate the coordination of cellular therapy with donor care. Ideally, these cells can sustain their activated state despite preservation, and without continuous exposure to the activating agent and/or co-administration of undesirable and/or clinically toxic agents, such that more general clinical applications might be possible.